Tetrahydro-naphthalene derivatives

ABSTRACT

This invention relates to tetrahydro-naphthalene derivatives and salts thereof which are useful as active ingredients of pharmaceutical preparations. They have the general formula (I) 
                         
in which R 1  represents hydrogen or C 1-6  alkyl, and X represents —N(H)Y 1 , —(H)—C 1-6  alkyleneY 1 , biphenyl or C 1-6  alkyl substituted by biphenyl, and the group Y 1  is an optionally substituted biphenyl. The tetrahydro-naphthalene derivatives of the present invention have excellent activity as VR1 antagonists and are useful for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urinary incontinence, overactive bladder, urge urinary incontinence, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, inflammatory disorders, asthma and COPD.

DETAILED DESCRIPTION OF INVENTION

1. Technical Field

The present invention relates to a tetrahydro-naphthalene derivativewhich is useful as an active ingredient of pharmaceutical preparations.The tetrahydro-naphthalene derivative of the present invention hasvanilloid receptor (VR) antagonistic activity, and can be used for theprophylaxis and treatment of diseases associated with VR1 activity, inparticular for the treatment of overactive bladder, urinaryincontinence, chronic pain, neuropathic pain, postoperative pain,rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerveinjury, ischaemia, neurodegeneration, stroke, urge urinary incontinence,and inflammatory disorders such as asthma and chronic obstructivepulmonary (or airways) disease (COPD).

2. Background Art

Vanilloid compounds are characterized by the presence of vanillyl groupor a functionally equivalent group. Examples of several vanilloidcompounds or vanilloid receptor modulators are vanillin(4-hydroxy-3-methoxy-benzaldehyde), guaiacol (2-methoxy-phenol),zingerone (4-/4-hydroxy-3-methoxyphenyl/-2-butanon),eugenol-(2-methoxy4-/2-propenyl/phenol), and capsaicin(8-methy-N-vanillyl-6-nonene-amide).

Among others, capsaicin, the main pungent ingredient in “hot” chilipeppers, is a specific neurotoxin that desensitizes C-fiber afferentneurons. Capsaicin interacts with vanilloid receptors (VR), which arepredominantly expressed in cell bodies of dorsal root ganglia (DRG) ornerve endings of afferent sensory fibers including C-fiber nerve endings[Tominaga M, Caterina M J, Malmberg A B, Rosen T A, Gilbert H, SkinnerK, Raumann B E, Basbaum A I, Julius D: The cloned capsaicin receptorintegrates multiple pain-producing stimuli. Neuron. 21: 531-543, 1998].The VR1 receptor was recently cloned [Caterina M J, Schumacher M A,Tominaga M, Rosen T A, Levine J D, Julius D: Nature 389: 816-824,(1997)] and identified as a non-selective cation channel with sixtransmembrane domains that is structurally related to the TRP (transientreceptor potential) channel family. Binding of capsaicin to VR1 allowssodium, calcium and possibly potassium ions to flow down theirconcentration gradients, causing initial depolarization and release ofneurotransmitters from the nerve terminals. VR1 can therefore be viewedas a molecular integrator of chemical and physical stimuli that elicitneuronal signals in a pathological conditions or diseases.

There are abundant of direct or indirect evidence that shows therelation between VR1 activity and diseases such as pain, ischaemia, andinflammatory (e.g., WO 99/00115 and 00/50387). Further, it has beendemonstrated that VR1 transduce reflex signals that are involved in theoveractive bladder of patients who have damaged or abnormal spinalreflex pathways [De Groat W C: A neurologic basis for the overactivebladder. Urology 50 (6A Suppl): 36-52, 1997]. Desensitisation of theafferent nerves by depleting neurotransmitters using VR1 agonists suchas capsaicin has been shown to give promising results in the treatmentof bladder dysfunction associated with spinal cord injury and multiplesclerosis [(Maggi C A: Therapeutic potential of capsaicin-likemolecules—Studies in animals and humans. Life Sciences 51: 1777-1781,1992) and (DeRidder D; Chandiramani V; Dasgupta P; VanPoppel H; Baert L;Fowler C J: Intravesical capsaicin as a treatment for refractorydetrusor hyperreflexia: A dual center study with long-term followup. J.Urol. 158: 2087-2092, 1997)].

It is anticipated that antagonism of the VR1 receptor would lead to theblockage of neurotransmitter release, resulting in prophylaxis andtreatment of the condition and diseases associated with VR1 activity.

It is therefore expected that antagonists of the VR1 receptor can beused for prophylaxis and treatment of the condition and diseasesincluding chronic pain, neuropathic pain, postoperative pain, rheumatoidarthritic pain, neuralgia, neuropathies, algesia, nerve injury,ischaemia, neurodegeneration, stroke, incontinence, inflammatorydisorders, urinary incontinence (UI) such as urge urinary incontinence(UUI), and/or overactive bladder.

UI is the involuntary loss of urine. UUI is one of the most common typesof UI together with stress urinary incontinence (SUI) which is usuallycaused by a defect in the urethral closure mechanism. UUI is oftenassociated with neurological disorders or diseases causing neuronaldamages such as dementia, Parkinson's disease, multiple sclerosis,stroke and diabetes, although it also occurs in individuals with no suchdisorders. One of the usual causes of UUI is overactive bladder (OAB)which is a medical condition referring to the symptoms of frequency andurgency derived from abnormal contractions and instability of thedetrusor muscle.

There are several medications for urinary incontinence on the markettoday mainly to help treating UUI. Therapy for OAB is focused on drugsthat affect peripheral neural control mechanisms or those that actdirectly on bladder detrusor smooth muscle contraction, with a majoremphasis on development of anticholinergic agents. These agents caninhibit the parasympathetic nerves which control bladder voiding or canexert a direct spasmolytic effect on the detrusor muscle of the bladder.This results in a decrease in intravesicular pressure, an increase incapacity and a reduction in the frequency of bladder contraction. Orallyactive anticholinergic drugs such as propantheline (ProBanthine),tolterodine tartrate (Detrol) and oxybutynin (Ditropan) are the mostcommonly prescribed drugs. However, their most serious drawbacks areunacceptable side effects such as dry mouth, abnormal visions,constipation, and central nervous system disturbances. These sideeffects lead to poor compliance. Dry mouth symptoms alone areresponsible for a 70% non-compliance rate with oxybutynin. Theinadequacies of present therapies highlight the need for novel,efficacious, safe, orally available drugs that have fewer side effects.

WO 00/50387 discloses the compounds having a vanilloid agonist activityrepresented by the general formula:

wherein;

-   X^(P) is an oxygen or sulfur atom;-   A^(P) is —NHCH₂— or —CH₂—;-   R^(a) is a substituted or unsubstituted C₁₋₄ alkyl group, or    R^(a1)CO—;    -   wherein    -   R^(a1) is an alkyl group having 1 to 18 carbon atoms, an alkenyl        group having 2 to 18 carbon atoms, or substituted or        unsubstituted aryl group having 6 to 10 carbon atoms;-   R^(b) is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,    an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having    1 to 6 carbon atoms or a halogen atom;-   R^(C) is a hydrogen atom, an alkyl group having 1 to 4 carbon atom,    an aminoalkyl, a diacid monoester or α-alkyl acid; and    the asterisk mark * indicates a chiral carbon atom, and their    pharmaceutically acceptable salts.

WO 2000/61581 discloses amine derivatives represented by the generalformula:

-   -   wherein    -   (R′, R″) represent (F, F), (CF₃, H), or (iPr, iPr)        as useful agents for diabetes, hyperlipemia, arteriosclerosis        and cancer.

WO 00/75106 discloses the compounds represented by the general formula:

wherein

-   Z represents

-   -   in which    -   R⁹⁰ is hydrogen, C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, or the like, and        R⁹¹ is amino-C₁₋₆ alkyl, aminocarbonyl-C₁₋₆ alkyl, or        hydroxyaminocarbonyl C₁₋₆ alkyl; and    -   R⁹⁰ and R⁹¹ are independently selected from the group consisting        of H, C₁₋₆ alkyl, C₁₋₆ alkylthio, C₁₋₆ alkoxy, fluoro, chloro,        bromo, iodo, and nitro;        as useful agents for treating MMP-mediated diseases in mammals.

WO 00/55152 discloses the compounds represented by the general formula:

wherein

-   Ar₁ is heterocycle;-   Ar₂ is tetrahydronapthyl; and-   L and Q are defined in this specification;    as useful agents for treating inflammation, immune related disease,    pain and diabetes.

However, none of these reference discloses simple tetrahydro-naphthalenederivatives having VR1 antagonistic activity.

The development of a compound which has effective VR1 antagonisticactivity and can be used for the prophylaxis and treatment of diseasesassociated with VR1 activity, in particular for the treatment of urinaryincontinence such as urge urinary incontinence, overactive bladder, aswell as pain, and/or inflammatory diseases such as asthma and COPD hasbeen desired.

SUMMARY OF THE INVENTION

This invention is to provide a tetrahydro-naphthalene derivative of theformula (I), their tautomeric and stereoisomeric form, and saltsthereof:

wherein

-   R¹ represents hydrogen or C₁₋₆ alkyl;-   X represents —N(H)Y¹, —N(H)—C₁₋₆ alkyleneY¹, biphenyl or C₁₋₆ alkyl    substituted by biphenyl;    -   wherein    -   said biphenyl is substituted by Z¹, Z² and Z³;    -   Y¹ represents biphenyl substituted by Z³, Z⁴ and Z⁵;        -   Z¹ and Z² are identical or different and represent hydrogen,            halogen, carboxy, nitro, C₁₋₆ alkyl optionally substituted            by cyano or mono-, di-, or tri-halogen, C₁₋₆ alkoxy            optionally substituted by morpholino, or mono-, di-, or            tri-halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino, di(C₁₋₆            alkyl)amino, C₁₋₆ alkylsulfinyl, C₁₋₆alkanoyl, or            C₁₋₆alkoxycarbonyl;        -   Z³ represents hydrogen, halogen, amino, pyrrolidinyl,            piperidino, piperazinyl, homopiperidino, C₁₋₆ alkoxy            optionally substituted by mono-, di-, or tri-halogen, or            C₁₋₆ alkyl optionally substituted by mono-, di-, or            tri-halogen;        -   Z⁴ represents halogen, carboxy, nitro, C₁₋₆ alkyl optionally            substituted by cyano or mono-, di-, or tri-halogen, C₁₋₆            alkoxy optionally substituted by morpholino, or mono-, di-,            or tri-halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino,            di(C₁₋₆ alkyl)-amino, C₁₋₆ alkylsulfinyl, C₁₋₆ alkanoyl, or            C₁₋₆ alkoxycarbonyl; and        -   Z⁵ represents hydrogen, halogen, carboxy, nitro, C₁₋₆ alkyl            optionally substituted by cyano or mono-, di-, or            tri-halogen, C₁₋₆ alkoxy optionally substituted by            morpholino, or mono-, di-, or tri-halogen, C₁₋₆ alkylthio,            amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆            alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl; or        -   Z⁴ and Z⁵ together with the carbon atom to which they are            attached, form a benzene ring.

The tetrahydro-naphthalene derivatives of formula (I), their tautomericand stereoisomeric form, and salts thereof surprisingly show excellentVR1 antagonistic activity. They are, therefore suitable especially forthe prophylaxis and treatment of diseases associated with VR1 activity,in particular for the treatment of urinary incontinence such as urgeurinary incontinence and/or overactive bladder.

The compounds of the present invention are also effective for treatingor preventing a disease selected from the group consisting of urinaryincontinence, overactive bladder, urge urinary incontinence, chronicpain, neuropathic pain, postoperative pain, rheumatoid arthritic pain,neuralgia, neuropathies, algesia, nerve injury, ischaemia,neurodegeneration and/or stroke, as well as inflammatory diseases suchas asthma and COPD since the diseases also relate to VR1 activity.

The compounds of the present invention are also useful for the treatmentand prophylaxis of neuropathic pain, which is a form of pain oftenassociated with herpes zoster and post-herpetic neuralgia, painfuldiabetic neuropathy, neuropathic low back pain, posttraumatic andpostoperative neuralgia, neuralgia due to nerve compression and otherneuralgias, phantom pain, complex regional pain syndromes, infectious orparainfectious neuropathies like those associated with HIV infection,pain associated with central nervous system disorders like multiplesclerosis or Parkinson disease or spinal cord injury or traumatic braininjury, and post-stroke pain.

Furthermore, the compounds of the present invention are useful for thetreatment of musculoskeletal pain, forms of pain often associated withosteoarthritis or rheumatoid arthritis or other forms of arthritis, andback pain.

In addition, the compounds of the present invention are useful for thetreatment of pain associated with cancer, including visceral orneuropathic pain associated with cancer or cancer treatment.

The compounds of the present invention are furthermore useful for thetreatment of visceral pain, e.g. pain associated with obstruction ofhollow viscus like gallstone colik, pain associated with irritable bowelsyndrome, pelvic pain, vulvodynia, orchialgia or prostatodynia, painassociated with inflammatory lesions of joints, skin, muscles or nerves,and orofascial pain and headache, e.g. migraine or tension-typeheadache.

Further, the present invention provides a medicament, which includes oneof the compounds, described above and optionally pharmaceuticallyacceptable excipients.

In another embodiment, the tetrahydro-naphthalene derivatives of formula(I) are those wherein;

-   R¹ represents hydrogen;-   X represents —N(H)Y¹ or —N(H)—C₁₋₆ alkyleneY¹;    -   Y¹ represents

-   -   -   Z³ represents hydrogen, fluoro, chloro, bromo, amino,            pyrrolidinyl, piperidino, piperazinyl, homopiperidino, C₁₋₆            alkoxy optionally substituted by cyano or mono-, di-, or            tri-halogen, or C₁₋₆ alkyl optionally substituted by cyano            or mono-, di-, or tri-halogen;        -   Z⁴ represents halogen, carboxy, nitro, C₁₋₆ alkyl optionally            substituted by cyano or mono-, di-, or tri-halogen, C₁₋₆            alkoxy optionally substituted by morpholino, or mono-, di-,            or tri-halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino,            di(C₁₋₆ alkyl)-amino, C₁₋₆alkylsulfinyl, C₁₋₆ alkanoyl, or            C₁₋₆alkoxycarbonyl; and        -   Z⁵ represents hydrogen, halogen, carboxy, nitro, C₁₋₆ alkyl            optionally substituted by cyano or mono-, di-, or            tri-halogen, C₁₋₆ alkoxy optionally substituted by            morpholino, or mono-, di-, or tri-halogen, C₁₋₆ alkylthio,            amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆            alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl.

Yet another embodiment of formula (I) can be those wherein:

-   R¹ represents hydrogen;-   X represents —N(H)Y¹ or —N(H)—C₁₋₆ alkyleneY¹;    -   Y¹ represents

-   -   -   Z³ represents hydrogen or piperidino;        -   Z⁴ represents fluoro, chloro, bromo, carboxy, nitro, C₁₋₆            alkyl optionally substituted by mono-, di-, or tri-halogen,            C₁₋₆ alkoxy optionally substituted by morpholino, or mono-,            di-, or tri-halogen, C₁₋₆ alkylthio, di(C₁₋₆ alkyl)amino,            C₁₋₆ alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl;            and        -   Z⁵ represents hydrogen, fluoro, chloro, bromo, C₁₋₆ alkoxy,            C₁₋₆ alkylthio or C₁₋₆ alkyl optionally substituted by cyano            or mono-, di-, or tri-halogen.

Further embodiment of the compounds of formula (I) is those wherein:

-   R¹ represents hydrogen;-   X represents

-   -   n represents an integer selected from 0 to 6;    -   Z¹ and Z² are identical or different and represent hydrogen,        fluoro, chloro, bromo, carboxy, nitro, C₁₋₆ alkyl optionally        substituted by mono-, di-, or tri-halogen, C₁₋₆ alkoxy        optionally substituted by morpholino, or mono-, di-, or        tri-halogen, C₁₋₆ alkylthio, di(C₁₋₆ alkyl)amino, C₁₋₆        alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl; and    -   Z³ represents hydrogen, fluoro, chloro, bromo, amino,        piperidino, C₁₋₆alkoxy optionally substituted by mono-, di-, or        tri-halogen, or C₁₋₆ alkyl optionally substituted by cyano or        mono-, di-, or tri-halogen.

Another embodiment of the compounds of formula (I) is those wherein:

-   R¹ represents hydrogen;-   X represents

-   -   n represents an integer of 0 or 1;    -   Z¹ represents hydrogen, fluoro, chloro, bromo, C₁₋₆alkyl, C₁₋₆        alkoxy, amino, C₁₋₆ alkylamino, or di(C₁₋₆ alkyl)amino;    -   Z² represents hydrogen, fluoro, chloro, bromo, C₁₋₆ alkyl or        C₁₋₆ alkoxy: and    -   Z³ represents hydrogen.

More preferably, said tetrahydro-naphthalene derivative of the formula(I) is selected from the group consisting of:

-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4′-(trifluoromethyl)biphenyl-3-yl]urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[2′-(trifluoromethyl)biphenyl-3-yl]urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4′-(methylthio)biphenyl-3-yl]urea;-   N-(2′,3′-dichlorobiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(2′,4′-dichlorobiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(4′-acetylbiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(2′-fluorobiphenyl-4-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(2′-fluorobiphenyl-4-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(2′,6′-difluorobiphenyl-4-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-[(2′-fluorobiphenyl-3-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;-   N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(4′-isopropylbiphenyl-3-yl)methyl]urea;-   N-[(2′,4′-dichlorobiphenyl-3-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea.

The Alkyl per se and “alk” and “alkyl” in alkoxy, alkanoyl, alkylamino,alkylaminocarbonyl, alkylaminosulphonyl, alkylsulphonylamino,alkoxycarbonyl, alkoxycarbonylamino and alkanoylamino represent a linearor branched alkyl radical having generally 1 to 6, preferably 1 to 4 andparticularly preferably 1 to 3 carbon atoms, representing illustrativelyand preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyland n-hexyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino illustratively and preferably represents an alkylaminoradical having one or two (independently selected) alkyl substituents,illustratively and preferably representing methylamino, ethylamino,n-propylamino, isopropylamino, tert-butyl-amino, n-pentylamino,n-hexyl-amino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino,N-isopropyl-N-n-propylamino, N-t-butyl-N-methylamino,N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

EMBODIMENT OF THE INVENTION

The compound of the formula (I) of the present invention can be, but notlimited to be, prepared by combining various known methods. In someembodiments, one or more of the substituents, such as amino group,carboxyl group, and hydroxyl group of the compounds used as startingmaterials or intermediates are advantageously protected by a protectinggroup known to those skilled in the art. Examples of the protectinggroups are described in “Protective Groups in Organic Synthesis (3rdEdition)” by Greene and Wuts, John Wiley and Sons, New York 1999.

The compound of the formula (I) of the present invention can be, but notlimited to be, prepared by the Method [A], [B], [C], [D], [E], [F], [G],[H], [I] or [J] below.

[Method A]

The compound of the formula (I-a) (wherein R¹, Z³, Z⁴, and Z⁵ are thesame as defined above and n represents an integer of 0 to 6) can beprepared by the reaction of the compound of the formula (II) (wherein R¹is the same as defined above) and the compound of the formula (VII)(wherein Z³, Z⁴, and Z⁵ are the same as defined above and n representsan integer of 0 to 6).

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction can be carried out in the presence of organic base such aspyridine or triethylamine.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about room temperature to 100° C. The reaction may beconducted for, usually, 30 minutes to 48 hours and preferably 1 to 24hours.

The compound (II) and (VII) can be prepared by the use of knowntechniques or are commercially available.

[Method B]

The compound of the formula (I-a) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) can be prepared by reacting the compound of theformula (II) (wherein R¹ is the same as defined above) with phosgene,diphosgene, triphosgene, 1,1-carbonyldiimidazole (CDI), or1,1′-carbonyldi(1,2,4-triazole)(CDT), and then adding the compound ofthe formula (VIII) (wherein n, Z³, Z⁴, and Z⁵ are the same as definedabove) to the reaction mixture.

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 50° C. The reaction may be conducted for,usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

Phosgene, diphosgene, triphosgene, CDI, CDT and the compound (VIII) arecommercially available or can be prepared by the use of knowntechniques.

[Method C]

The compound of the formula (I-a) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) can be prepared by reacting the compound of theformula (II) (wherein R¹ is the same as defined above) and the compoundof the formula (IX) (wherein L₁ represents halogen atom such aschlorine, bromine, or iodine atom) and then adding the compound of theformula (VI) (wherein n, Z³, Z⁴, and Z⁵ are the same as defined above)to the reaction mixture.

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 50° C. The reaction may be conducted for,usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The reaction can be advantageously carried out in the presence of a baseincluding, for instance, organic amines such as pyridine, triethylamineand N,N-diisopropylethylamine, dimethylaniline, diethylaniline,4-dimethylaminopyridine, and others.

The compound (IX) is commercially available or can be prepared by theuse of known techniques.

[Method D]

The compound of the formula (I-a) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) can be prepared by reacting the compound of theformula (VIII) (wherein n, Z³, Z⁴, and Z⁵ are the same as defined above)with phosgene, diphosgene, triphosgene, 1,1-carbonyldiimidazole (CDI),or 1,1′-carbonyldi(1,2,4-triazole)(CDT), and then adding the compound ofthe formula (II) (wherein R¹ is the same as defined above) to thereaction mixture.

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 50° C. The reaction may be conducted for,usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

[Method E]

The compound of the formula (I-a) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) can be prepared by reacting the compound of theformula (VIII) (wherein n, Z³, Z⁴, and Z⁵ are the same as defined above)and the compound of the formula (IX) (wherein L₁ is the same as definedabove), and then adding the compound of the formula (II) (wherein R¹ isthe same as defined above) to the reaction mixture.

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitrites such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 50° C.

The reaction may be conducted for, usually, 30 minutes to 10 hours andpreferably 1 to 24 hours.

The reaction can be advantageously carried out in the presence of a baseincluding, for instance, organic amines such as pyridine, triethylamineand N,N-diisopropylethylamine, dimethylaniline, diethylaniline,4-dimethylaminopyridine, and others.

[Method F]

The compound of the formula (I-a) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) can be prepared by the following procedures inthree steps;

In the Step F-1, the compound of the formula (XI) (wherein R¹, Z³, Z⁴,and Z⁵ are the same as defined above and n represents an integer of 0 to6) can be prepared by reacting the compound of the formula (X) (whereinR¹ is the same as defined above) with the compound of the formula (VII)(wherein n, R¹, Z³, Z⁴, and Z⁵ are the same as defined above) in asimilar manner described in Method A for the preparation of the compoundof the formula (I-a).

In the Step F-2, the compound of the formula (XII) (wherein n, R¹, Z³,Z⁴, and Z⁵ are the same as defined above) can be prepared by reactingthe compound of the formula (XI) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) with an acid such as hydrochloric acid.

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; alcohols suchas methanol, ethanol; water and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 100° C. The reaction may be conducted for,usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

In the Step F-3, the compound of the formula (I-a) (wherein n, R¹, Z³,Z⁴, and Z⁵ are the same as defined above) can be prepared by reactingthe compound of the formula (XII) (wherein n, R¹, Z³, Z⁴, and Z⁵ are thesame as defined above) with reducing agent such as sodium borohydride orlithium aluminum hydride.

The reaction may be carried out in a solvent including, for instance,ethers such as diethyl ether, isopropyl ether, dioxane andtetrahydrofuran (THF) and 1,2-dimethoxyethane; alcohols such asmethanol, ethanol, isopropanol, and others. Optionally, two or more ofthe solvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 50° C.

The reaction may be conducted for, usually, 30 minutes to 10 hours andpreferably 1 to 24 hours.

The compound (X) is commercially available or can be prepared by the useof known techniques.

[Method G]

The stereoisomeric form of the compound (I-a), R form (I-a-i) (whereinn, R¹, Z³, Z⁴, and Z⁵ are the same as defined above) can be prepared bythe reaction of the compound of the formula (II-i) (wherein R¹ is thesame as defined above) with the compound of the formula (VII) (whereinn, Z³, Z⁴, and Z⁵ are the same as defined above) in a similar mannerdescribed in Method A for the preparation of the compound of the formula(I-a).

The stereoisomeric form of the compound (I-a), S form (I-a-ii) (whereinn, R¹, Z³, Z⁴, and Z⁵ are the same as defined above) can be prepared bythe reaction of the compound of (II-ii) (wherein R¹ is the same asdefined above) with the compound of the formula (VII) (wherein n, R¹,Z³, Z⁴, and Z⁵ are the same as defined above) in a similar mannerdescribed in Method A for the preparation of the compound of the formula(I-a).

The compound (II-i) or (II-ii) can be prepared by the use of knowntechniques.

[Method H]

The compound of the formula (I-a′) (wherein R¹, Z⁴ and Z⁵ are the sameas defined above and n represents an integer of 0 to 6) can be obtainedby the reaction of the compound of the formula (IV) (wherein n and R¹are the same as defined above and L represents a leaving groupincluding, for example, halogen atom such as chlorine, bromine, oriodine atom; and C₁₋₄ alkylsulfonyloxy group, e.g.,trifluoromethanesulfonyloxy, methanesulfonyloxy and the like) with thecompound of the formula (III-a) (wherein Z⁴ and Z⁵ are the same asdefined above and M represents metal group including, for instance,organoborane group such as boronic acid and dimethoxy boryl;organostannyl group such as tributyl stannyl, and the like.) in thepresence of a palladium catalyst such astetrakis(triphenylphosphine)palladium.

The reaction can be advantageously carried out in the presence of a baseincluding, for instance, cesium carbonate, sodium carbonate andpotassium carbonate, barium hydroxide and the like.

The reaction may be carried out in a solvent including, for instance,ethers such as diethyl ether, isopropyl ether, dioxane andtetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbonssuch as benzene, toluene and xylene; amides such asN,N-dimethylformamide (DMF), N,N-dimethylacetamide andN-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO);alcohols such as methanol, ethanol, 1-propanol, isopropanol andtert-butanol; water and others. Optionally, two or more of the solventsselected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 20° C. to 120° C. The reaction may be conducted for,usually, 30 minutes to 48 hours and preferably 1 to 24 hours.

The compound (III-a) is commercially available or can be prepared by theuse of known techniques.

[Method I]

The compound (I-b) (wherein n, R¹, Z¹, Z², and Z³ are the same asdefined above and n represents an integer of 0 to 6), can be prepared bythe reaction of the compound of the formula (II) (wherein R¹ is the sameas defined above) with the compound of the formula (V) (wherein Z¹, Z²,and Z³ are the same as defined above, n represents an integer of 0 to 6and L₂ represents a leaving group including, for instance, hydroxy orhalogen atom such as chlorine, bromine, or iodine atom).

The reaction may be carried out in a solvent including, for instance,halogenated hydrocarbons such as dichloromethane, chloroform and1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether,dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatichydrocarbons such as benzene, toluene and xylene; nitriles such asacetonitrile; amides such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides such asdimethylsulfoxide (DMSO); and others. Optionally, two or more of thesolvents selected from the listed above can be mixed and used.

The reaction temperature can be optionally set depending on thecompounds to be reacted. The reaction temperature is usually, but notlimited to, about 0° C. to 50° C. The reaction may be conducted for,usually, 30 minutes to 10 hours and preferably 1 to 24 hours.

The reaction can be advantageously carried out in the presence of a baseincluding, for instance, organic amines such as pyridine, triethylamineand N,N-diisopropylethylamine, dimethylaniline, diethylaniline,4-dimethylaminopyridine, and others.

When L₂ is hydroxy, the reaction can be advantageously carried out usingcoupling agent including, for instance, hydroxybenzotriazole,carbodiimides such as N,N-dicyclohexylcarbodiimide and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide; carbonyldiazoles such as1,1′-carbonyldi(1,3-imiazole)(CDI) and1,1′-carbonyldi-(1,2,4-triazole)(CDT), and the like.

The compound (V) is commercially available or can be prepared by the useof known techniques.

[Method J]

The compound (I-b′) wherein (wherein R¹, Z¹ and Z¹ are the same asdefined above and n represents an integer of 0 to 6), can be obtained byin two steps;

In the step J-1, the compound of the formula (VI) (wherein n and R¹ arethe same as defined above), can be prepared by the reaction of thecompound of the formula (II) (wherein R¹ is the same as defined above)with the compound of the formula (V′) (wherein L is a leaving group asdefined above, n represents an integer of 0 to 6 and L₂ represents aleaving group including, for instance, hydroxy or halogen atom such aschlorine, bromine, or iodine atom;) in a similar manner described inMethod I for the preparation of the compound of the formula (I-b).

In the step J-2, the compound of the formula (I-b′) (wherein R¹, Z¹, Z²and n are the same as defined above), can be prepared by the reaction ofthe compound of the formula (VI) (wherein R¹, L and n are the same asdefined above) with the compound of the formula (III-b) (wherein Z¹, Z²and M are the same as defined above) in a similar manner described inMethod A for the preparation of the compound of the formula (I-a).

The compound (V′) and (III-b) are commercially available or can beprepared by the use of known techniques.

Preparation of the Compound of the Formula (IV)

The compound of the formula (IV) of the present invention can be, butnot limited to be, prepared by Method [K], [L], [M], [N], [O], [P] or[Q] below.

[Method K]

The compound of the formula (IV) (wherein n, R¹ and L are the same asdefined above) can be prepared by the reaction of the compound of theformula (II) (wherein R¹ is the same as defined above) and the compoundof the formula (VII′) (wherein L is the same as defined above and nrepresents an integer of 0 to 6) in a similar manner described in MethodA for the preparation of the compound of the formula (I-a).

The compound (VII′) can be prepared by the use of known techniques or iscommercially available.

[Method L]

The compound (IV) (wherein n, R¹ and L are the same as defined above)can be prepared by reacting the compound of the formula (II) (wherein R¹is the same as defined above) with phosgene, diphosgene, triphosgene,1,1-carbonyldiimidazole (CDI), or 1,1′-carbonyldi(1,2,4-triazole) (CDT),and then adding the compound of the formula (VIII′) (wherein L is thesame as defined above and n represents an integer of 0 to 6) to thereaction mixture in a similar manner described in Method B for thepreparation of the compound of the formula (I-a).

The compound (VIII′) is commercially available or can be prepared by theuse of known techniques.

[Method M]

The compound (IV) (wherein n, R¹ and L are the same as defined above)can be prepared by reacting the compound of the formula (II) (wherein R¹is the same as defined above) and the compound of the formula (IX)(wherein L₁ is are the same as defined above) and then adding thecompound of the formula (VIII′) (wherein L and n are the same as definedabove) to the reaction mixture in a similar manner described in Method Cfor the preparation of the compound of the formula (I-a).

[Method N]

The compound (I) (wherein n, R¹ and L are the same as defined above) canbe prepared by reacting the compound of the formula (VIII′) (wherein Land n are the same as defined above) with phosgene, diphosgene,triphosgene, 1,1-carbonyldiimidazole (CDI), or1,1′-carbonyldi(1,2,4-triazole)(CDT), and then adding the compound ofthe formula (II) (wherein R¹ is the same as defined above) to thereaction mixture in a similar manner described in Method D for thepreparation of the compound of the formula (I-a).

[Method O]

The compound (IV) (wherein n, R¹ and L are the same as defined above)can be prepared by reacting the compound of the formula (VIII′) (whereinL and n are the same as defined above) and the compound of the formula(IX) (wherein L₁ is the same as defined above), and then adding thecompound of the formula (II) (wherein R¹ is the same as defined above)to the reaction mixture in a similar manner described in Method E forthe preparation of the compound of the formula (I-a).

[Method P]

The compound (IV) (wherein n, R¹ and L are the same as defined above)can be prepared by the following procedures in three steps;

In the step P-1, the compound of the formula (XI′) (wherein n, R¹ and Lare the same as defined above) can be prepared by reacting the compoundof the formula (X) (wherein R¹ is the same as defined above) with thecompound of the formula (VII′) (wherein L and n are the same as definedabove) in a similar manner described in Method A for the preparation ofthe compound of the formula (I-a).

In the step P-2, the compound of the formula (XII′) (wherein n, R¹ and Lare the same as defined above) can be prepared by reacting the compoundof the formula (XI′) (wherein n, R¹ and L are the same as defined above)with an acid such as hydrochloric acid in a similar manner described inMethod F step F-2 for the preparation of the compound of the formula(XII).

In the step P-3: the compound of the formula (I) (wherein n, R¹ and Lare the same as defined above) can be prepared by reacting the compoundof the formula (XII′) (wherein n, R¹ and L are the same as definedabove) with reducing agent such as sodium borohydride or lithiumaluminum hydride in a similar manner described in Method F step F-3 forthe preparation of the compound of the formula (I-a)

[Method Q]

The stereoisomeric form of the compound (IV), R form (IV-i) (wherein n,R¹ and L are the same as defined above) can be prepared by the reactionof the compound of the formula (II-i) (wherein R¹ is the same as definedabove) with the compound of the formula (VII′) (wherein L and n are thesame as defined above) in a similar manner described in Method A for thepreparation of the compound of the formula (I-a).

The stereoisomeric form of the compound (IV), S form (IV-ii) (wherein n,R¹ and L are the same as defined above) can be prepared by the reactionof the compound of (II-ii) (wherein R¹ is the same as defined above)with the compound of the formula (VII′) (wherein L and n are the same asdefined above) in a similar manner described in Method A for thepreparation of the compound of the formula (I-a).

When the compound shown by the formula (I) or a salt thereof has anasymmetric carbon in the structure, their optically active compounds andracemic mixtures are also included in the scope of the presentinvention.

When the compound shown by the formula (I) or a salt thereof has anasymmetric carbon in the structure, their optically active compounds andracemic mixtures are also included in the scope of the presentinvention.

Typical salts of the compound shown by the formula (I) include saltsprepared by reaction of the compounds of the present invention with amineral or organic acid, or an organic or inorganic base. Such salts areknown as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as,without limitation, sulfuric acid, phosphoric acid, hydrochloric acid,hydrobromic acid, hydriodic acid and the like, and organic acids, suchas, without limitation, p-toluenesulfonic acid, methanesulfonic acid,oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid,citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as,without limitation, ammonium hydroxide, alkaline metal hydroxide,alkaline earth metal hydroxides, carbonates, bicarbonates, and the like,and organic bases, such as, without limitation, ethanolamine,triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examplesof inorganic bases include sodium hydroxide, potassium hydroxide,potassium carbonate, sodium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salt thereof, depending onits substituents, may be modified to form lower alkylesters or knownother esters; and/or hydrates or other solvates. Those esters, hydrates,and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms,such as, without limitation normal and enteric coated tablets, capsules,pills, powders, granules, elixirs, tinctures, solution, suspensions,syrups, solid and liquid aerosols and emulsions. They may also beadministered in parenteral forms, such as, without limitation,intravenous, intraperitoneal, subcutaneous, intramuscular, and the likeforms, well-known to those of ordinary skill in the pharmaceutical arts.The compounds of the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using transdermal delivery systems well-known to those ofordinary skilled in the art.

The dosage regimen with the use of the compounds of the presentinvention is selected by one of ordinary skill in the arts, in view of avariety of factors, including, without limitation, age, weight, sex, andmedical condition of the recipient, the severity of the condition to betreated, the route of administration, the level of metabolic andexcretory function of the recipient, the dosage form employed, theparticular compound and salt thereof employed.

The compounds of the present invention are preferably formulated priorto administration together with one or more pharmaceutically-acceptableexcipients. Excipients are inert substances such as, without limitationcarriers, diluents, flavoring agents, sweeteners, lubricants,solubilizers, suspending agents, binders, tablet disintegrating agentsand encapsulating material.

Yet another embodiment of the present invention is pharmaceuticalformulation comprising a compound of the invention and one or morepharmaceutically-acceptable excipients that are compatible with theother ingredients of the formulation and not deleterious to therecipient thereof. Pharmaceutical formulations of the invention areprepared by combining a therapeutically effective amount of thecompounds of the invention together with one or morepharmaceutically-acceptable excipients therefore. In making thecompositions of the present invention, the active ingredient may bemixed with a diluent, or enclosed within a carrier, which may be in theform of a capsule, sachet, paper, or other container. The carrier mayserve as a diluent, which may be solid, semi-solid, or liquid materialwhich acts as a vehicle, or can be in the form of tablets, pillspowders, lozenges, elixirs, suspensions, emulsions, solutions, syrups,aerosols, ointments, containing, for example, up to 10% by weight of theactive compound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with anoral, and non-toxic, pharmaceutically-acceptable carrier, such as,without limitation, lactose, starch, sucrose, glucose, sodium carbonate,mannitol, sorbitol, calcium carbonate, calcium phosphate, calciumsulfate, methyl cellulose, and the like; together with, optionally,disintegrating agents, such as, without limitation, maize, starch,methyl cellulose, agar bentonite, xanthan gum, alginic acid, and thelike; and optionally, binding agents, for example, without limitation,gelatin, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic gums, acacia, tragacanth, sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is inadmixture with the finely divided active ingredient. The activeingredient may be mixed with a carrier having binding properties insuitable proportions and compacted in the shape and size desired toproduce tablets. The powders and tablets preferably contain from about 1to about 99 weight percent of the active ingredient which is the novelcomposition of the present invention. Suitable solid carriers aremagnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carriers, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physicallydiscrete unit containing a unit dose, suitable for administration inhuman or other mammals. A unit dosage form can be a capsule or tablets,or a number of capsules or tablets. A “unit dose” is a predeterminedquantity of the active compound of the present invention, calculated toproduce the desired therapeutic effect, in association with one or moreexcipients. The quantity of active ingredient in a unit dose may bevaried or adjusted from about 0.1 to about 1000 milligrams or moreaccording to the particular treatment involved.

Typical oral dosages of the present invention, when used for theindicated effects, will range from about 0.01 mg/kg/day to about 100mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and mostpreferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the caseof parenteral administration, it has generally proven advantageous toadminister quantities of about 0.001 to 100 mg/kg/day, preferably from0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present inventionmay be administered in a single daily dose, or the total daily dose maybe administered in divided doses, two, three, or more times per day.Where delivery is via transdermal forms, of course, administration iscontinuous.

EXAMPLES

The present invention will be described as a form of examples, but theyshould by no means be construed as defining the metes and bounds of thepresent invention.

In the examples below, all quantitative data, if not stated otherwise,relate to percentages by weight.

Mass spectra were obtained using electrospray (ES) ionization techniques(micromass Platform LC). Melting points are uncorrected. LiquidChromatography-Mass spectroscopy (LC-MS) data were recorded on aMicromass Platform LC with Shimadzu Phenomenex ODS column(4.6 mmφ×30 mm)flushing a mixture of acetonitrile-water (9:1 to 1:9) at 1 ml/min of theflow rate. TLC was performed on a precoated silica gel plate (Mercksilica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was usedfor all column chromatography separations. All chemicals were reagentgrade and were purchased from Sigma-Aldrich, Wako pure chemicalindustries, Ltd., Great Britain, Tokyo kasei kogyo Co., Ltd., Nacalaitesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge plc, LancasterSynthesis Ltd., Merck KgaA, Germany, Kanto Chemical Co., Ltd.

¹H NMR spectra were recorded using either Bruker DRX-300 (300 MHz for¹H) spectrometer or Brucker 500 UltraShieled™ (500 MHz for 1H). Chemicalshifts are reported in parts per million (ppm) with tetramethylsilane(TMS) as an internal standard at zero ppm. Coupling constant (J) aregiven in hertz and the abbreviations s, d, t, q, m, and br refer tosinglet, doblet, triplet, quartet, multiplet, and broad, respectively.The mass determinations were carried out by MAT95 (Finnigan MAT).

All starting materials are commercially available or can be preparedusing methods cited in the literature.

The effect of the present compounds were examined by the followingassays and pharmacological tests.

[Measurement of Capsaicin-Induced Ca²⁺ influx in the HumanVR1-Transfected CHO Cell Line] (Assay 1)

(1) Establishment of the Human VR1-CHOluc9aeq cell line

-   -   Human vanilloid receptor (hVR1) cDNA was cloned from libraries        of axotomized dorsal root ganglia (WO 00/29577). The cloned hVR1        cDNA was constructed with pcDNA3 vector and transfected into a        CHOluc9aeq cell line. The cell line contains aequorin and        CRE-luciferase reporter genes as read-out signals. The        transfectants were cloned by limiting dilution in selection        medium (DMEM/F12 medium (Gibco BRL) supplemented with 10% FCS,        1.4 mM Sodium pyruvate, 20 mM HEPES, 0.15% Sodium bicarbonate,        100 U/ml penicillin, 100 μg/ml streptomycin, 2 mM glutamine,        non-essential amino acids and 2 mg/ml G418). Ca²⁺ influx was        examined in the capsaicin-stimulated clones. A high responder        clone was selected and used for further experiments in the        project. The human VR1-CHOluc9aeq cells were maintained in the        selection medium and passaged every 3-4 days at 1-2.5×10⁵        cells/flask (75 mm²).        (2) Measurement of Ca²⁺ Influx Using FDSS-3000    -   Human VR1-CHOluc9aeq cells were suspended in a culture medium        which is the same as the selection medium except for G418 and        seeded at a density of 1,000 cells per well into 384-well plates        (black walled clear-base/Nalge Nunc International). Following        the culture for 48 hrs the medium was changed to 2 μM Fluo-3 AM        (Molecular Probes) and 0.02% Puronic F-127 in assay buffer        (Hank's balanced salt solution (HBSS), 17 mM HEPES (pH7.4), 1 mM        Probenecid, 0.1% BSA) and the cells were incubated for 60 min at        25° C. After washing twice with assay buffer the cells were        incubated with a test compound or vehicle for 20 min at 25° C.        Mobilization of cytoplasmic Ca²⁺ was measured by FDSS-3000        (λ_(ex)=488 nm, λ_(em)=540 nm/Hamamatsu Photonics) for 60 sec        after the stimulation with 10 nM capsaicin. Integral R was        calculated and compared with controls.        [Measurement of the Capsaicin-Induced Ca²⁺ Influx in Primary        Cultured Rat Dorsal Root Ganglia Neurons] (Assay 2)        (1) Preparation of Rat Dorsal Root Ganglia Neurons    -   New born Wister rats (5-11 days) were sacrificed and dorsal root        ganglia (DRG) was removed. DRG was incubated with 0.1% trypsin        (Gibco BRL) in PBS(−) (Gibco BRL) for 30 min at 37° C., then a        half volume of fetal calf serum (FCS) was added and the cells        were spun down. The DRG neuron cells were resuspended in Ham        F12/5% FCS/5% horse serum (Gibco BRL) and dispersed by repeated        pipetting and passing through 70 μm mesh (Falcon). The culture        plate was incubated for 3 hours at 37° C. to remove        contaminating Schwann cells. Non-adherent cells were recovered        and further cultured in laminin-coated 384 well plates (Nunc) at        1×10⁴ cells/50 μl/well for 2 days in the presence of 50 ng/ml        recombinant rat NGF (Sigma) and 50 μM 5-fluorodeoxyuridine        (Sigma).        (2) Ca²⁺ Mobilization Assay    -   DRG neuron cells were washed twice with HBSS supplemented with        17 mM HEPES (pH 7.4) and 0.1% BSA. After incubating with 2 μM        fluo-3AM (Molecular Probe), 0.02% PF127 (Gibco BRL) and 1 mM        probenecid (Sigma) for 40 min at 37° C., cells were washed 3        times. The cells were incubated with VR1 antagonists or vehicle        (dimethylsulphoxide) and then with 1 μM capsaicin in FDSS-6000        (λ_(ex)=480 nm, λ_(em)=520 nm/Hamamatsu Photonics). The        fluorescence changes at 480 nm were monitored for 2.5 min.        Integral R was calculated and compared with controls.        [Organ Bath Assay to Measure the Capsaicin-Induced Bladder        Contraction] (Assay 3)

Male Wistar rats (10 week old) were anesthetized with ether andsacrificed by dislocating the necks. The whole urinary bladder wasexcised and placed in oxygenated Modified Krebs-Henseleit solution (pH7.4) of the following composition (112 mM NaCl, 5.9 mM KCl, 1.2 mMMgCl₂, 1.2 mM NaH₂PO₄, 2 mM CaCl₂, 2.5 mM NaHCO₃, 12 mM glucose).Contractile responses of the urinary bladder were studied as describedpreviously [Maggi C A et al: Br. J. Pharmacol. 108: 801-805, 1993].Isometric tension was recorded under a load of 1 g using longitudinalstrips of rat detrusor muscle. Bladder strips were equilibrated for 60min before each stimulation. Contractile response to 80 mM KCl wasdetermined at 15 min intervals until reproducible responses wereobtained. The response to KCl was used as an internal standard toevaluate the maximal response to capsaicin. The effects of the compoundswere investigated by incubating the strips with compounds for 30 minprior to the stimulation with 1 μM capsaicin (vehicle: 80% saline, 10%EtOH, and 10% Tween 80). One of the preparations made from the sameanimal was served as a control while the others were used for evaluatingcompounds. Ratio of each capsaicin-induced contraction to the internalstandard (i.e. KCl-induced contraction) was calculated and the effectsof the test compounds on the capsaicin-induced contraction wereevaluated.

[Measurement of Ca²⁺ Influx in the Human P2X1-Transfected CHO Cell Line]

(1) Preparation of the Human P2X1-Transfected CHOluc9aeq Cell Line

-   -   Human P2X1-transfected CHOluc9aeq cell line was established and        maintained in Dulbecco's modified Eagle's medium (DMEM/F12)        supplemented with 7.5% FCS, 20 mM HEPES-KOH (pH 7.4), 1.4 mM        sodium pyruvate, 100 U/ml penicillin, 100 μg/ml streptomycin, 2        mM glutamine (Gibco BRL) and 0.5 Units/ml apyrase (grade I,        Sigma). The suspended cells were seeded in each well of 384-well        optical bottom black plates (Nalge Nunc International) at        3×10³/50 μl/well. The cells were cultured for following 48 hrs        to adhere to the plates.        (2) Measurement of the Intracellular Ca²⁺ Levels    -   P2X1 receptor agonist-mediated increases in cytosolic Ca²⁺        levels were measured using a fluorescent Ca²⁺ chelating dye,        Fluo-3 AM (Molecular Probes). The plate-attached cells were        washed twice with washing buffer (HBSS, 17 mM HEPES-KOH (pH        7.4), 0.1% BSA and 0.5 units/ml apyrase), and incubated in 40 μl        of loading buffer (1 μM Fluo-3 AM, 1 mM probenecid, 1 μM        cyclosporin A, 0.01% pluronic (Molecular Probes) in washing        buffer) for 1 hour in a dark place. The plates were washed twice        with 40 μl washing buffer and 35 μl of washing buffer were added        in each well with 5 μl of test compounds or        2′,3′-o-(2,4,6-trinitrophenyl) adenosine 5′-triphpsphate        (Molecular Probes) as a reference. After further incubation for        10 minutes in dark 200 nM α, β-methylene ATP agonist was added        to initiate the Ca²⁺ mobilization. Fluorescence intensity was        measured by FDSS-6000 (λ_(ex)=410 mm, λ_(em)=510 nm/Hamamatsu        Photonics) at 250 msec intervals. Integral ratios were        calculated from the data and compared with that of a control.        [Measurement of Capsaicin-Induced Bladder Contraction in        Anesthetized Rats] (Assay 4)        (1) Animals    -   Female Sprague-Dawley rats (200˜250 g/Charles River Japan) were        used.        (2) Catheter Implantation    -   Rats were anesthetized by intraperitoneal administration of        urethane (Sigma) at 1.2 g/kg. The abdomen was opened through a        midline incision, and a polyethylene catheter (BECTON DICKINSON,        PE50) was implanted into the bladder through the dome. In        parallel, the inguinal region was incised, and a polyethylene        catheter (Hibiki, size 5) filled with 2 IU/ml of heparin (Novo        Heparin, Aventis Pharma) in saline (Otsuka) was inserted into a        common iliac artery.        (3) Cystometric Investigation    -   The bladder catheter was connected via T-tube to a pressure        transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a        microinjection pump (TERUMO). Saline was infused at room        temperature into the bladder at a rate of 2.4 ml/hr.        Intravesical pressure was recorded continuously on a chart pen        recorder (Yokogawa). At least three reproducible micturition        cycles, corresponding to a 20-minute period, were recorded        before a test compound administration and used as baseline        values.        (4) Administration of Test Compounds and Stimulation of Bladder        with Capsaicin    -   The saline infusion was stopped before administrating compounds.        A testing compound dissolved in the mixture of ethanol, Tween 80        (ICN Biomedicals Inc.) and saline (1:1:8, v/v/v) was        administered intraarterially at 10 mg/kg. 2 min after the        administration of the compound 10 μg of capsaicin (Nacalai        Tesque) dissolved in ethanol was administered intraarterially.        (5) Analysis of Cystometry Parameters    -   Relative increases in the capsaicin-induced intravesical        pressure were analyzed from the cystometry data. The        capsaicin-induced bladder pressures were compared with the        maximum bladder pressure during micturition without the        capsaicin stimulation. The testing compounds-mediated inhibition        of the increased bladder pressures was evaluated using Student's        t-test. A probability level less than 5% was accepted as        significant difference.        [Measurement of Over Active Bladder in Anesthetized Cystitis        Rats] (Assay 5)        (1) Animals    -   Female Sprague-Dawley rats (180˜250 g/Charles River Japan) were        used. Cyclophosphamide (CYP) dissolved in saline was        administered intraperitoneally at 150 mg/kg 48 hours before        experiment.        (2) Catheter Implantation    -   Rats were anesthetized by intraperitoneal administration of        urethane (Sigma) at 1.25 g/kg. The abdomen was opened through a        midline incision, and a polyethylene catheter (BECTON DICKINSON,        PE50) was implanted into the bladder through the dome. In        parallel, the inguinal region was incised, and a polyethylene        catheter (BECTON DICKINSON, PE50) filled with saline (Otsuka)        was inserted into a femoral vein. After the bladder was emptied,        the rats were left for 1 hour for recovery from the operation.        (3) Cystometric Investigation    -   The bladder catheter was connected via T-tube to a pressure        transducer (Viggo-Spectramed Pte Ltd, DT-XXAD) and a        microinjection pump (TERUMO). Saline was infused at room        temperature into the bladder at a rate of 3.6 ml/hr for 20 min.        Intravesical pressure was recorded continuously on a chart pen        recorder (Yokogawa). At least three reproducible micturition        cycles, corresponding to a 20-minute period, were recorded        before a test compound administration.        (4) Administration of Test Compounds    -   A testing compound dissolved in the mixture of ethanol, Tween 80        (ICN Biomedicals Inc.) and saline (1:1:8, v/v/v) was        administered intravenously at 0.05 mg/kg, 0.5 mg/kg or 5 mg/kg.        3 min after the administration of the compound, saline (Nacalai        Tesque) was infused at room temperature into the bladder at a        rate of 3.6 ml/hr.        (5) Analysis of Cystometry Parameters    -   The cystometry parameters were analyzed as described previously        [Lecci A et al: Eur. J. Pharmacol. 259: 129-135, 1994]. The        micturition frequency calculated from micturition interval and        the bladder capacity calculated from a volume of infused saline        until the first micturition were analyzed from the cystometry        data. The testing compounds-mediated inhibition of the frequency        and the testing compounds-mediated increase of bladder capacity        were evaluated using unpaired Student's t-test. A probability        levels less than 5% was accepted as significant difference. Data        were analyzed as the mean± SEM from 4-7 rats.        [Measurement of Acute Pain]

Acute pain is measured on a hot plate mainly in rats. Two variants ofhot plate testing are used: In the classical variant animals are put ona hot surface (52 to 56° C.) and the latency time is measured until theanimals show nocifensive behavior, such as stepping or foot licking. Theother variant is an increasing temperature hot plate where theexperimental animals are put on a surface of neutral temperature.Subsequently this surface is slowly but constantly heated until theanimals begin to lick a hind paw. The temperature which is reached whenhind paw licking begins is a measure for pain threshold.

Compounds are tested against a vehicle treated control group. Substanceapplication is performed at different time points via differentapplication routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal,transdermal) prior to pain testing.

[Measurement of Persistent Pain]

Persistent pain is measured with the formalin or capsaicin test, mainlyin rats. A solution of 1 to 5% formalin or 10 to 100 μg capsaicin isinjected into one hind paw of the experimental animal. After formalin orcapsaicin application the animals show nocifensive reactions likeflinching, licking and biting of the affected paw. The number ofnocifensive reactions within a time frame of up to 90 minutes is ameasure for intensity of pain.

Compounds are tested against a vehicle treated control group. Substanceapplication is performed at different time points via differentapplication routes (i.v., i.p., p.o., i.t., i.c.v., s.c., intradermal,transdermal) prior to formalin or capsaicin administration.

[Measurement of Neuropathic Pain]

Neuropathic pain is induced by different variants of unilateral sciaticnerve injury mainly in rats. The operation is performed underanesthesia. The first variant of sciatic nerve injury is produced byplacing loosely constrictive ligatures around the common sciatic nerve(Bennett and Xie, Pain 33 (1988): 87-107). The second variant is thetight ligation of about the half of the diameter of the common sciaticnerve (Seltzer et al., Pain 43 (1990): 205-218). In the next variant, agroup of models is used in which tight ligations or transections aremade of either the L5 and L6 spinal nerves, or the L5 spinal nerve only(KIM S H; CHUNG J M, AN EXPERIMENTAL-MODEL FOR PERIPHERAL NEUROPATHYPRODUCED BY SEGMENTAL SPINAL NERVE LIGATION IN THE RA, PAIN 50 (3)(1992): 355-363). The fourth variant involves an axotomy of two of thethree terminal branches of the sciatic nerve (tibial and common peronealnerves) leaving the remaining sural nerve intact whereas the lastvariant comprises the axotomy of only the tibial branch leaving thesural and common nerves uninjured. Control animals are treated with asham operation.

Postoperatively, the nerve injured animals develop a chronic mechanicalallodynia, cold allodynioa, as well as a thermal hyperalgesia.Mechanical allodynia is measured by means of a pressure transducer(electronic von Frey Anesthesiometer, IITC Inc.-Life ScienceInstruments, Woodland Hills, SA, USA; Electronic von Frey System,Somedic Sales AB, Hörby, Sweden). Thermal hyperalgesia is measured bymeans of a radiant heat source (Plantar Test, Ugo Basile, Comerio,Italy), or by means of a cold plate of 5 to 10° C. where the nocifensivereactions of the affected hind paw are counted as a measure of painintensity. A further test for cold induced pain is the counting ofnocifensive reactions, or duration of nocifensive responses afterplantar administration of acetone to the affected hind limb. Chronicpain in general is assessed by registering the circadanian rhytms inactivity (Surjo and Arndt, Universität zu Köln, Cologne, Germany), andby scoring differences in gait (foot print patterns; FOOTPRINTS program,Klapdor et al., 1997. A low cost method to analyse footprint patterns.J. Neurosci. Methods 75, 49-54).

Compounds are tested against sham operated and vehicle treated controlgroups. Substance application is performed at different time points viadifferent application routes (i.v., i.p., p.o., i.t., i.c.v., s.c.,intradermal, transdermal) prior to pain testing.

[Measurement of Inflammatory Pain]

Inflammatory pain is induced mainly in rats by injection of 0.75 mgcarrageenan or complete Freund's adjuvant into one hind paw. The animalsdevelop an edema with mechanical allodynia as well as thermalhyperalgesia. Mechanical allodynia is measured by means of a pressuretransducer (electronic von Frey Anesthesiometer, IITC Inc.-Life ScienceInstruments, Woodland Hills, SA, USA). Thermal hyperalgesia is measuredby means of a radiant heat source (Plantar Test, Ugo Basile, Comerio,Italy, Paw thermal stimulator, G. Ozaki, University of California, USA).For edema measurement two methods are being used. In the first method,the animals are sacrificed and the affected hindpaws sectioned andweighed. The second method comprises differences in paw volume bymeasuring water displacement in a plethysmometer (Ugo Basile, Comerio,Italy).

Compounds are tested against uninflamed as well as vehicle treatedcontrol groups. Substance application is performed at different timepoints via different application routes (i.v., i.p., p.o., i.t., i.c.v.,s.c., intradermal, transdermal) prior to pain testing.

[Measurement of Diabetic Neuropathic Pain]

Rats treated with a single intraperitoneal injection of 50 to 80 mg/kgstreptozotocin develop a profound hyperglycemia and mechanical allodyniawithin 1 to 3 weeks. Mechanical allodynia is measured by means of apressure transducer (electronic von Frey Anesthesiometer, IITC Inc.-LifeScience Instruments, Woodland Hills, SA, USA).

Compounds are tested against diabetic and non-diabetic vehicle treatedcontrol groups. Substance application is performed at different timepoints via different application routes (i.v., i.p., p.o., i.t., i.c.v.,s.c., intradermal, transdermal) prior to pain testing.

Results of IC₅₀ of capsaicin-induced Ca²⁺ influx in the humanVR1-transfected CHO cell line are shown in Examples and tables of theExamples below. The data corresponds to the compounds as yielded bysolid phase synthesis and thus to levels of purity of about 40 to 90%.For practical reasons, the compounds are grouped in four classes ofactivity as follows:IC_(50=A) (< or =) 0.1 μM<B (< or =) 0.5 μM<C (< or =) 1 μM<D

The compounds of the present invention also show excellent selectivity,and strong activity in other assays 2-5 described above.

Z used in melting point in the following section indicatesdecomposition.

Preparation of Compounds

[Starting Compound A]

(7-Ethoxy-5,8-dihydronaphthalen-1-yl)amine

To a stirred solution of 8-amino-2-naphthol (50.0 g, 314 mmol) intetrahydrofuran (1000 mL) was added di-t-butyldicarbonate (68.6 g, 314mmol). The mixture was stirred at 70° C. for 18 hours. After the mixturewas cooled to room temperature, solvent was removed under reducedpressure. To the residue was added ethylacetate, and washed withsaturated aqueous solution of sodium carbonate and then with water. Theextracted organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. To the obtained residue was addeddiisopropyl ether, and the precipitate was filtered and dried to affordtert-butyl(7-hydroxy-1-naphthyl)carbamate (64.2 g, 79% yield).

Next, to a mixture of tert-butyl (7-hydroxy-1-naphthyl)carbamate (64.0g, 247 mmol) and cesium carbonate (161 g, 493 mmol) in 300 mL anhydrousDMF was added iodoethane (42.3 g, 272 mmol) at room temperature. Themixture was stirred at 60° C. for 2 hours. Water was added to themixture, and the product was extracted with ethylacetate. The organiclayer was washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. To the obtained residue was addeddiisopropyl ether and the precipitate was collected and dried to affordtert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9 g, 67.5% yield).

Next, to a solution of tert-butyl (7-ethoxy-1-naphthyl)carbamate (47.9g, 167 mmol) in 100 mL anhydrous 1,4-dioxane was added 4N HCl in1,4-dioxane (100 mL) at 0° C. The mixture was stirred at roomtemperature for 2 hours. Diisopropyl ether was added to the reactionmixture and the precipitate was filtered. To the obtained solid wasadded saturated sodium bicarbonate and the product was extracted withethylacetate. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford (7-ethoxy-1-naphthyl)amine(27.0 g, 86.3% yield).

Next, to a flask containing a mixture of (7-ethoxy-1-naphthyl)amine(1.80 g, 9.61 mmol) and t-buthanol (2.13 g, 28.8 mmol) intetrahydrofuran (20 mL) was collected liquid ammonia (300 mL) at −78° C.To the mixture was added lithium (0.200 g, 28.8 mmol) over 30 minutesand stirred at −78° C. for 1 hour. Methanol and water was added, and themixture was stirred at room temperature for 16 hours to allow ammonia toevaporate. To the obtained residue was added ethylacetate. The organiclayer was washed with water, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to afford(7-ethoxy-5,8-dihydronaphthalen-1-yl)amine (1.37 g, 76% yield).

[Starting Compound B]

8-Amino-1,2,3,4-tetrahydro-naphthalen-2-ol

To a stirred solution of (7-ethoxy-5,8-dihydronaphthalen-1-yl)amine(1.07 g, 5.65 mmol) in tetrahydrofuran (30 mL) was added solution ofaqueous 2N HCl (10 mL), and stiired at 40° C. for 1 hour. The mixturewas neutralized with addition of sodium bicorbonate, and the product wasextracted with ethylacetate. The organic layer was washed with water,dried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.71 g, 78% yield).

Next, to 8-amino-3,4-dihydronaphthalen-2(1H)-one (0.050 g, 0.318 mmol)in methanol (10 mL) was added sodium borohydride (0.030 g, 0.175 mmol)at 0° C., and the mixture was stirred for 1 hour. The mixture was pouredinto water, and the product was extracted with ethylacetate. The organiclayer was dried over Na₂SO₄, filtered, and concentrated under reducedpressure to afford 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (0.037 g,71% yield).

[Starting Compound C]

8-Amino-1,2,3,4-tetrahydro-naphthalen-2-ol chiral enantiomer

To a stirred solution of benzeneruthenium(II) chloride dimer (3.10 mg,0.006 mmol) and (1S, 2R)-(−)-cis-1-amino-2-indanol (3.7 mg, 0.025 mmol)in degaussed isopropanol was heated at 80° C. for 20 minutes underargon. The mixture was added to the solution of8-amino-3,4-dihydronaphthalen-2(1H)-one (50 mg, 0.310 mmol) inisopropanol (3 mL) at room temperature. A solution of potassiumhydroxide (3.48 mg, 0.062 mmol) in isopropanol (1 mL) was added, and themixture was stired at 45° C. for 1 hour. The mixture was passed throughsilica gel and washed with ethylacetate. The filtrate was concentratedunder reduced pressure to afford the8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol chiral enantiomer (33.0 mg,65% yield).

Example 1-1N-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(4′-methylbiphenyl-3-yl)urea

To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol(30.0 mg, 0.18 mmol) and pyridine (21.8 mg, 0.28 mmol) in 1.0 mL THF wasadded phenyl chloroformate (30.2 mg, 0.19 mmol), and the mixture wasstirred for 1 hour at room temperature. To the product mixture was addedwater and extracted with ethylacetate. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The obtained residue was triturated with ethylacetate andhexane to afford phenyl(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (25.2 mg, 48%yield).

Next, a mixture of phenyl(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamate (30.0 mg, 0.11mmol) and 3-iodoaniline (25.5 mg, 0.12 mmol) in 0.2 mL of DMSO washeated at 100° C. for 16 hours. After cooled to room temperature, waterwas added and the product was extracted with ethylacetate. The organiclayer was washed with water then brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to obtainN-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea(20.3 mg, 47% yield).

Next, to a solution ofN-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(3-iodophenyl)urea(9.0 mg, 0.02 mmol) and 4-tolylboronic acid (3.60 mg, 0.03 mmol) in THFwas added tetrakis(triphenylphosphine)palladium(0) (2.55 mg) followed by0.1 mL of saturated sodium bicarbonate solution. The mixture was stirredfor 3 hours at 90° C., then ethylacetate was added. The mixture waspassed through a short pad of silica gel and was concentrated underreduced pressure to affordN-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(4′-methylbiphenyl-3-yl)urea(2.80 mg, 34% yield).

-   -   mp 217-219° C.;    -   Molecular weight: 372.47    -   MS (M+H): 373    -   Activity Class: A

In the similar manner as described in Example 1-1, compounds in Example1-2 to 1-76 as shown in Table 1 were synthesized.

TABLE 1 MS Activity Ex-No. Structure MW (M + H) mp (° C.) Class 1-2 

430.51 431 198-200 A 1-3 

410.88 411 94-96 A 1-4 

402.45 403 281-284 A 1-5 

394.42 395 187-189 A 1-6 

430.51 431 142-144 A 1-7 

426.44 427 amorphous A 1-8 

392.89 393 amorphous A 1-9 

426.44 427 amorphous A 1-10

404.54 405 amorphous A 1-11

394.42 395 amorphous A 1-12

386.5 387 221 A 1-13

388.47 389 204 A 1-14

388.47 389 203 A 1-15

418.5 419 190 A 1-16

376.43 377 228 A 1-17

394.42 395 216 A 1-18

392.89 393 209 A 1-19

427.33 428 221 A 1-20

427.33 428 204 A 1-21

427.33 428 208 A 1-22

427.33 428 209 A 1-23

426.44 427 210 A 1-24

442.44 443 195 A 1-25

442.44 443 210 A 1-26

401.51 402 215 A 1-27

400.48 401 216 A 1-28

403.44 404 238 A 1-29

487.6 488 >127Z A 1-30

415.54 416 205-206 A 1-31

402.5 403 215-216 A 1-32

386.5 387 211-212 A 1-33

406.92 407 195-196 A 1-34

441.36 442 139-140 A 1-35

402.5 403 128-129 A 1-36

432.52 433 113-114 A 1-37

400.53 401 181-182 A 1-38

390.46 391 191-192 A 1-39

456.47 457 218-219 A 1-40

441.36 442 177-178 A 1-41

408.45 409 191-192 A 1-42

424.91 425 205-206 A 1-43

456.47 457 199-200 A 1-44

440.47 441 196-197 A 1-45

390.46 391 201-202 A 1-46

418.56 419 216-217 A 1-47

432.52 433 205-206 C 1-48

390.46 391 187-188 A 1-49

408.45 409 191-192 A 1-50

408.45 409 204-205 A 1-51

400.53 401 205-206 A 1-52

414.55 415 202-203 A 1-53

441.36 442 204-205 A 1-54

417.47 418 206-207 A 1-55

390.46 391 194-195 A 1-56

456.47 457 175-176 A 1-57

415.54 416 207-208 A 1-58

456.47 457 188-189 A 1-59

508.47 509 208-209 A 1-60

432.52 433 123-124 A 1-61

402.5 403 129-130 A 1-62

432.52 433 223-224 A 1-63

417.47 418 191-192 A 1-64

408.45 409 197-198 A 1-65

408.45 409 188-189 A 1-66

390.46 391 197-198 A 1-67

400.53 401 197-198 A 1-68

418.56 419 195-196 A 1-69

408.45 409 141-142 A 1-70

414.55 415 202-203 A 1-71

424.91 425 188-189 A 1-72

441.36 442 152-153 A 1-73

402.5 403 188-189 A 1-74

434.56 435 110-112 A 1-75

408.5 409 223 A 1-76

501.7 502 113-115 A

Example 2-13′,4′-Difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide

To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol(1.00 g, 6.13 mmol) in 30 mL THF was added pyridine (0.727 g, 9.19 mmol)and then cooled to 0° C. To the mixture was added 4-iodobenzolylchloride (1.94 g, 7.29 mmol) and was slowly warmed to room temperature.After stirred for 1 hour, the mixture was poured into water, and theproduct was extracted with ethylacetate. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The product was triturated with ethylacetate and hexane, andthe resulting solid was collected to affordN-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (2.06 g,80% yield).

Next, to a solution ofN-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-iodobenzamide (100 mg,0.25 mmol) in a 3 to 1 mixture of DMF and H₂O was added3,4-difluorophenylboronic acid (80.3 mg, 0.51 mmol),tetrakis(triphenylphosphine)palladium(0) (8.82 mg, 0.01 mmol), andsodium carbonate (80.9 mg, 0.76 mmol). The mixture was stirred at 80° C.for 2.5 hours, and after cooled to room temperature, the product wasextracted with diethyl ether. The organic layer was washed with waterthen brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. After triturated with ethylacetate and hexane, the solid wasfiltered to afford3′,4′-difluoro-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)biphenyl-4-carboxamide(51.9 mg, 54%).

¹H NMR (DMSO-d₆) δ 1.53-1.68 (m, 1H), 1.84-1.94 (m, 1H), 2.80 (dd,J=9.3, 5.2 Hz, 1H), 2.86-2.91 (m, 1H), 2.91-2.97 (m, 1H), 3.29 (s, 1H),3.83-3.94 (m, 1H), 4.77 (d, J=3.9 Hz, 1H), 7.02 (dd, J=6.2, 2.6 Hz, 1H),7.14 (d, J=3.4 Hz, 1H), 7.15 (s, 1H), 7.52-7.68 (m, 2H), 7.87 (d, J=8.5Hz, 2H), 7.92 (dd, J=7.8, 2.2 Hz, 1H), 8.08 (d, J=8.5 Hz, 2H), 9.84 (s,1H).

-   -   mp 210.4-212.7° C.;    -   Molecular weight: 379.4    -   MS (M+H): 380    -   Activity Class: A

In the similar manner as described in Example 2-1, compounds in Example2-2 to 2-5 as shown in Table 2 were synthesized.

TABLE 2 MS Activity Ex-No. Structure MW (M + H) mp (° C.) Class 2-2

386.5 387 222.1-225.0 A 2-3

387.48 388 150.0-151.2 C 2-4

343.43 344 215-217 A 2-5

373.46 374 193.3-196.5 C

Example 3-12-Biphenyl-3-yl-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide

To a stirred solution of 8-amino-1,2,3,4-tetrahydro-naphthalen-2-ol (500mg, 3.06 mmol) and 3-bromophenylacetic acid (725 mg, 3.37 mmol) in DMFwas added triethylamine (465 mg, 4.60 mmol), 1-hydroxybenzotriazole (497mg, 3.68 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (705 mg, 3.68 mmol). The mixture was stirred for 16 hoursat room temperature. To the product mixture was added water andextracted with ethylacetate. The organic layer was washed with aqueousHCl solution then aqueous NaOH solution and brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The product waspurified by silica gel column chromatography (hexane:acetone, 2:1) toafford2-(3-bromophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide(130 mg, 12% yield).

Next, to a mixture of2-(3-bromophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide(50.0 mg, 0.139 mmol), phenyl boronic acid (25.4 mg, 0.208 mmol),tri-o-tolylphosphine (8.45 mg, 0.028 mmol), and barium hydroxideoctahydrate (65.7 mg, 0.208 mmol) in 12 mL of ethylene glycol dimethylether was added ethanol (4 mL), water (4 mL), and palladium(II) acetate(3.12 mg, 0.014 mmol). The mixture was stirred vigorously under argonand was heated to reflux. After cooled to room temperature, water wasadded and the product was extracted with ethylacetate. The organic layerwas washed with water then brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure to obtain2-biphenyl-3-yl-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide(13.0 mg, 26% yield).

¹H NMR (DMSO-d₆) δ 1.60 (m, 1H), 1.84 (m, 1H), 2.72-2.89 (m, 4H), 3.75(s, 2H), 3.88 (m, 1H), 4.79 (d, J=4.1 Hz, 1H), 6.90 (d, J=7.1 Hz, 1H),7.04 (t, J=7.5 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 7.37-7.56 (m, 7H), 7.66(d, J=7.1 Hz, 2H), 9.40 (s, 1H).

-   -   mp>134° C. decomp.    -   Molecular weight: 357.45    -   MS (M+H): 358    -   Activity Class: C

In the similar manner as described in Example 3-1, compounds in Example3-2 as shown in Table 3 was synthesized.

TABLE 3 MS Activity Ex-No. Structure MW (M + H) mp (° C.) Class 3-2

375.45 376 >103Z C

1. A tetrahydro-naphthalenyl derivative of the formula (I), itstautomeric or stereoisomeric form, or a salt thereof:

wherein R¹ represents hydrogen or C₁₋₆ alkyl; X represents —N(H)Y¹,—N(H)—C₁₋₆ alkyleneY¹, biphenyl or C₁₋₆ alkyl substituted by biphenyl;wherein said biphenyl is substituted by Z¹, Z² or Z³; Y¹ representsbiphenyl substituted by Z³, Z⁴ or Z⁵; Z¹ and Z² are identical ordifferent and represent hydrogen, halogen, carboxy, nitro, C₁₋₆ alkyloptionally substituted by cyano or mono-, di-, or tri- halogen, C₁₋₆alkoxy optionally substituted by morpholino, or mono-, di-, or tri-halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,C₁₋₆ alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₆ alkoxycarbonyl; Z³ representshydrogen, halogen, amino, pyrrolidinyl, piperidino, piperazinyl,homopiperidino, C₁₋₆ alkoxy optionally substituted by mono-, di-, ortri- halogen, or C₁₋₆ alkyl optionally substituted by mono-, di-, ortri- halogen; Z⁴ represents halogen, carboxy, nitro, C₁₋₆ alkyloptionally substituted by cyano or mono-, di-, or tri- halogen, C₁₋₆alkoxy optionally substituted by morpholino, or mono-, di-, or tri-halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,C₁₋₆ alkylsulfinyl, C₁₋₆alkanoyl, or C₁₋₆alkoxycarbonyl; and Z⁵represents hydrogen, halogen, carboxy, nitro, C₁₋₆ alkyl optionallysubstituted by cyano or mono-, di-, or tri- halogen, C₁₋₆ alkoxyoptionally substituted by morpholino, or mono-, di-, or tri- halogen,C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl; or Z⁴ and Z₅together with the carbon atom to which they are attached, form a benzenering.
 2. The tetrahydro-naphthalenyl derivative of the formula (I) itstautomeric or stereoisomeric form, or a salt thereof as claimed in claim1, wherein R¹ represents hydrogen; X represents —N(H)Y¹ or —N(H)—C₁₋₆alkyleneY¹; Y¹ represents

Z³ represents hydrogen, fluoro, chloro, bromo, amino, pyrrolidinyl,piperidino, piperazinyl, homopiperidino, C₁₋₆ alkoxy optionallysubstituted by cyano or mono-, di-, or tri- halogen, or C₁₋₆ alkyloptionally substituted by cyano or mono-, di-, or tri- halogen; Z⁴represents halogen, carboxy, nitro, C₁₋₆ alkyl optionally substituted bycyano or mono-, di-, or tri- halogen, C₁₋₆ alkoxy optionally substitutedby morpholino, or mono-, di-, or tri- halogen, C₁₋₆ alkylthio, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, C₁₋₆ alkylsulfinyl, C₁₋₆alkanoyl,or C₁₋₆ alkoxycarbonyl; and Z⁵ represents hydrogen, halogen, carboxy,nitro, C₁₋₆ alkyl optionally substituted by cyano or mono-, di-, or tri-halogen, C₁₋₆ alkoxy optionally substituted by morpholino, or mono-,di-, or tri- halogen, C₁₋₆ alkylthio, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, C₁₋₆ alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl.3. The tetrahydro-naphthalenyl derivative of the formula (I) itstautomeric or stereoisomeric form, or a salt thereof as claimed in claim1, wherein R¹ represents hydrogen; X represents —N(H)Y¹ or —N(H)—C₁₋₆alkyleneY¹; Y¹ represents

Z³ represents hydrogen or piperidino; Z⁴ represents fluoro, chloro,bromo, carboxy, nitro, C₁₋₆ alkyl optionally substituted by mono-, di-,or tri- halogen, C₁₋₆ alkoxy optionally substituted by morpholino, ormono-, di-, or tri- halogen, C₁₋₆ alkylthio, di(C₁₋₆ alkyl)amino, C₁₋₆alkylsulfinyl, C₁₋₆ alkanoyl, or C₁₋₆ alkoxycarbonyl; and Z⁵ representshydrogen, fluoro, chloro, bromo, C₁₋₆ alkoxy, C₁₋₆ alkylthio or C₁₋₆alkyl optionally substituted by cyano or mono-, di-, or tri- halogen. 4.The tetrahydro-naphthalenyl derivative of the formula (I) its tautomericor stereoisomeric form, or a salt thereof as claimed in claim 1, whereinR¹ represents hydrogen; X represents

n represents an integer selected from 0 to 6; Z¹ and Z² are identical ordifferent and represent hydrogen, fluoro, chloro, bromo, carboxy, nitro,C₁₋₆ alkyl optionally substituted by mono-, di-, or tri- halogen, C₁₋₆alkoxy optionally substituted by morpholino, or mono-, di-, or tri-halogen, C₁₋₆ alkylthio, di(C₁₋₆ alkyl)amino, C₁₋₆ alkylsulfinyl, C₁₋₆alkanoyl, or C₁₋₆ alkoxycarbonyl; and Z³ represents hydrogen, fluoro,chloro, bromo, amino, piperidino, C₁₋₆ alkoxy optionally substituted bymono-, di-, or tri- halogen, or C₁₋₆ alkyl optionally substituted bycyano or mono-, di-, or tri- halogen.
 5. The tetrahydro-naphthalenylderivative of the formula (I), its tautomeric or stereoisomeric form, ora salt thereof as claimed in claim 1, wherein R¹ represents hydrogen; Xrepresents

n represents an integer of 0 or 1; Z¹ represents hydrogen, fluoro,chloro, bromo, C₁₋₆alkyl, C₁₋₆ alkoxy, amino, C₁₋₆ alkylamino, ordi(C₁₋₆ alkyl)amino; Z² represents hydrogen, fluoro, chloro, bromo, C₁₋₆alkyl or C₁₋₆ alkoxy; and Z³ represents hydrogen.
 6. Thetetrahydro-naphthalenyl derivative of the formula (I), its tautomeric orstereoisomeric form, or a salt thereof as claimed in claim 1, whereinsaid tetrahydro-naphthalenyl derivative of the formula (I) is selectedfrom the group consisting of:N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4′-(trifluoromethyl)-biphenyl-3-yl]urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[2′-(trifluoromethyl)-biphenyl-3-yl]urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[4′-(methylthio)-biphenyl-3-yl]urea;N-(2′,3′-dichlorobiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(2′,4′-dichlorobiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(4′-acetylbiphenyl-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[(2′-fluorobiphenyl-4-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[(2′,6′-difluorobiphenyl-4-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-[(2′-fluorobiphenyl-3-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[(4′-isopropylbiphenyl-3-yl)methyl]urea; andN-[(2′,4′-dichlorobiphenyl-3-yl)methyl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea.7. A pharmaceutical composition comprising a tetrahydro-naphthalenederivative of the formula (I), its tautomeric or stereoisomeric form, ora physiologically acceptable salt thereof as claimed in claim 1 as anactive ingredient, and a pharmaceutically acceptable carrier.
 8. Thepharmaceutical composition as claimed in claim 7, wherein saidtetrahydro-naphthalene derivative of the formula (I), its tautomeric orstereoisomeric form, or a physiologically acceptable salt thereof is aVR1 antagonist.